c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas

• Published in: Oncotarget Vol. 8; no. 4; pp. 6940 - 6954
• Main Authors: Heiland, Dieter H, Ferrarese, Roberto, Claus, Rainer, Dai, Fangping, Masilamani, Anie P, Kling, Eva, Weyerbrock, Astrid, Kling, Teresia, Nelander, Sven, Carro, Maria S
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 24.01.2017
• Subjects: Anisomycin - pharmacology; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Cell Line, Tumor; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA Methylation - drug effects; DNMT1; Epigenesis, Genetic - drug effects; Female; G-CIMP; Gene Expression Regulation, Neoplastic - drug effects; Genome, Human; Glioblastoma; Glioma - genetics; Glioma - metabolism; Humans; mesenchymal; p-c-Jun; Phosphorylation; Prognosis; Promoter Regions, Genetic - drug effects; Proto-Oncogene Proteins c-jun - metabolism; Research Paper; Survival Analysis; Up-Regulation - drug effects; p-c-Jun; DNMT1; mesenchymal; G-CIMP; Glioblastoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.14330

High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.